Novel KCNQ2 and KCNQ3 Mutations in a Large Cohort of Families with Benign Neonatal Epilepsy: First Evidence for an Altered Channel Regulation by Syntaxin‐1A

Mutations in the KCNQ2 and KCNQ3 genes encoding for K_v7.2 (KCNQ2; Q2) and K_v7.3 (KCNQ3; Q3) voltage‐dependent K⁺ channel subunits, respectively, cause neonatal epilepsies with wide phenotypic heterogeneity. In addition to benign familial neonatal epilepsy (BFNE), KCNQ2 mutations have been recently found in families with one or more family members with a severe outcome, including drug‐resistant seizures with psychomotor retardation, electroencephalogram (EEG) suppression‐burst pattern (Ohtahara syndrome), and distinct neuroradiological features, a condition that was named “KCNQ2 encephalopathy.” In the present article, we describe clinical, genetic, and functional data from 17 patients/families whose electroclinical presentation was consistent with the diagnosis of BFNE. Sixteen different heterozygous mutations were found in KCNQ2, including 10 substitutions, three insertions/deletions and three large deletions. One substitution was found in KCNQ3. Most of these mutations were novel, except for four KCNQ2 substitutions that were shown to be recurrent. Electrophysiological studies in mammalian cells revealed that homomeric or heteromeric KCNQ2 and/or KCNQ3 channels carrying mutant subunits with newly found substitutions displayed reduced current densities. In addition, we describe, for the first time, that some mutations impair channel regulation by syntaxin‐1A, highlighting a novel pathogenetic mechanism for KCNQ2‐related epilepsies.     

Emergence of stable interfaces under extreme plastic deformation

Atomically ordered bimetal interfaces typically develop in near-equilibrium epitaxial growth (bottom-up processing) of nanolayered composite films and have been considered responsible for a number of intriguing material properties. Here, we discover that interfaces of such atomic level order can also emerge ubiquitously in large-scale layered nanocomposites fabricated by extreme strain (top down) processing. This is a counterintuitive result, which we propose occurs because extreme plastic straining creates new interfaces separated by single crystal layers of nanometer thickness. On this basis, with atomic-scale modeling and crystal plasticity theory, we prove that the preferred bimetal interface arising from extreme strains corresponds to a unique stable state, which can be predicted by two controlling stability conditions. As another testament to its stability, we provide experimental evidence showing that this interface maintains its integrity in further straining (strains > 12), elevated temperatures (> 0.45 T_m of a constituent), and irradiation (light ion). These results open a new frontier in the fabrication of stable nanomaterials with severe plastic deformation techniques.Unlike traditional materials, nanomaterials contain an unusually high density of interfaces that give rise to unprecedented properties such as ultrahigh strengths (1–5). Further, nanomaterials with nearly perfect, atomically ordered low-energy interfaces have been found to possess extraordinary thermal stability and radiation tolerance (1, 6–10). However, nanomaterials with disordered, high-energy interfaces are not stable in these same extreme conditions (11, 12). The integrity of the interface is tied to how the nanomaterial was made. Near-equilibrium processes generate perfect interfaces prevailing across the material but only produce small amounts of material, such as epitaxial thin films (13, 14). Ordinary large-scale metal-working (far from equilibrium) processes produce large amounts of nanostructured material suitable for technical application, but the interface types can vary within the same sample. For single-phase metals, the heavy straining can drive dislocations generated during deformation to organize into low-energy boundary structures (15, 16), some of which can be ordered (17) and others disordered (12, 18–20). Likewise, in heavily drawn two-phase composites, several kinds of bimetal interface structures have been reported, both ordered and disordered (21). Achieving uniformly ordered interfaces in bulk nanostructured metals presents a grand challenge in the design of materials that can be stable in the harsh environments demanded by the next generation of highly energy-efficient systems.Here we discover that a bulk metal-working technique that imposes extreme amounts of plastic strains can give rise to a preferred bimetal interface with perfect atomic order. Most remarkably, experimental evidence shows that this preferred interface occurs ubiquitously throughout the volume (>cm³) of the nanocomposite. This interface is shown to be stable with respect to further straining, high-temperature exposure, and irradiation, giving the nanomaterial extraordinary tolerances in other extreme situations. This finding has the exciting potential of eliminating the aforementioned tradeoff and permitting the creation of materials with pristine interfaces in stable nanocomposites of unlimited quantities. However, although such bulk deformation techniques may offer flexibility in processing path, current approaches for linking strain path to the resulting metallic microstructures have been empirical. To fundamentally rationalize this seemingly counterintuitive result, we use theory, atomic-scale modeling, and experimental characterization to identify the stability conditions that govern the emergence of a preferred interface at extreme strains. We reveal that the observed interface indeed corresponds to a special stable state. On a grander scale, this insight can be used to create other stable interfaces and open a new frontier of deformation processing for extreme-tolerant materials.To impose extreme strains, we fabricated Cu–Nb nanolayered materials in bulk form (>cm³) with a severe plastic deformation processing (SPD) technique called accumulative roll bonding (ARB; refs. 22–24). We begin with an alternating stack of sheets of these two dissimilar, immiscible metals, and then carry out the ARB process. Unlike conventional rolling, ARB strains the sample via a cycle of rolling, cutting, and restacking, and maintains the original sample dimensions. To prevent oxide contamination at the interfaces during the entire ARB process, we use a specially designed method (SI Text and Fig. S1). The individual layer thickness h can be easily refined and controlled with increasing strain (Fig. S1).Previously SPD techniques, like ARB, have been used to make fine-layered material (h = 10–10² μm) using large strains but a significant fraction of the interfaces was reported to be disordered and dispersed (18–22). Here we impose extreme strains, decreasing h by 5–6 orders of magnitude, from 2 mm to 20 nm. This is equivalent to stretching a nickel coin to 2.2 km in length (or strains exceeding 12).As a way of measuring the degree of microstructural ordering, neutron diffraction was first used to nondestructively measure the distribution of crystallographic orientations (texture) of all grains in the entire ARB sheet. To investigate size effects, these measurements were repeated for samples with different internal layer dimension h, ranging from h = 100 μm to 20 nm. The results revealed that a transition from the classical texture distribution (25–28) to an unfamiliar distribution takes place at h = 700 nm (or a strain of 8) (23). The new texture was exceptionally sharp, signifying a highly oriented structure. This is in stark contrast to the range of orientations that usually stabilize in Cu or Nb when rolled alone.To help understand the texture transition, we use electron backscatter diffraction (EBSD), which, in addition to texture, can locate orientations and phases within the microstructure (29–32). With EBSD, we found that the transition is coincident with attainment of layers that are spanned by only one grain. The grains are exceedingly wide, with an average aspect ratio of 30, about 5–10 times that expected in conventional rolling. This length scale is also below that (∼1 μm) at which dislocation density and substructure development within the layers between interfaces gradually decrease (23, 24) until, at fine layers (200 nm and below), they were no longer observed (refs. 30, 32; see Fig. 4A). This means that at the transition point, individual grains have become bounded by interfaces and not ordinary grain boundaries. These measurements suggest that the unexpectedly, highly oriented microstructure is influenced by the close proximity of the bimetal interfaces.Open in a separate windowFig. 4.Staying stable in extremes. Transmission electron microcopy micrographs displaying the planar Cu–Nb interfaces after (A) extreme plastic strains of ∼12, which produces an h = 20 nm composite, (B) elevated temperatures of 500 °C, which is 0.45 times the melting temperature of Cu (32), and (C) helium-ion irradiation, showing no voids in the layer or in the interfaces in an h = 20 nm composite (39).To determine whether preferred orientations correlate with preferred interfaces; that is, whether certain Cu and Nb orientations prefer to be joined, we carried out a correlation analysis of the paired Cu and Nb orientations on either side of the interfaces. For statistical significance, we obtained the data from numerous Cu–Nb pairs from several EBSD maps of samples with h below but near the transition point (29). The extraordinary outcome was that the Cu and Nb orientations were highly correlated. Most of the Cu and Nb grains have assembled such that they are bonded at their mutual {112} planes and the <111> direction of Cu is aligned with the <110> direction of Nb. This means that the Cu orientation on one side of the interface is {112}<111> and the Nb orientation on the other side is {112}<110>. These measurements find that the distribution about these preferred orientations is narrow, such that each crystal varies within 0.1–0.2% of the entire orientation space. Such a highly oriented state is peculiar because many orientations in Cu and Nb are expected to be stable in rolling (25–28) and hence the number of possible Cu–Nb orientation combinations among them is expected to be large. In contradiction, we find that a singular interface character, as defined by this pairing of a particular Cu and Nb orientation, is strongly preferred.To see whether this preferred interface character is stable with respect to straining, we repeated characterization for samples varying in individual layer thickness from h = 200 nm to h = 20 nm. These samples experienced correspondingly strains of 9–12, above and beyond that of conventional rolling. Because these fine nanoscale dimensions of h reached the limits of EBSD, we used other techniques, such as wedge-mounting EBSD (30) and precession electron diffraction (PED) (31), as well as transmission electron microscopy (TEM) and high-resolution (HR)-TEM (32, 33), to obtain analogous measurements. These measurements revealed that the layers remained one grain thick and their average aspect ratio increased to at least 80, meaning the bimetal interface density increased and the grain boundary density decreased markedly. More importantly, they showed that refinement to nanoscale dimensions strengthened the predominance of this preferred interface. Evidently, this special interface character is stable with respect to straining. It was remarkable to note that extreme strains invoke a natural selection process for particular interfaces.To assess the atomic structure of this interface, we use HR-TEM to observe the interfaces in several nanomaterial samples (different h < 100 nm). Fig. 1 shows HR-TEM micrographs of the preferred interface; two configurations are shown, which are slightly misoriented by ∼7°. The unexpected result is that they are regularly ordered at the atomic level. Typically after severe plastic deformation of metals, a fraction of the grain boundaries are disordered (18–22). The atomic regularity in Fig. 1 is reminiscent of pristine, low-energy bimetal interfaces formed after near-equilibrium, thermodynamic processes (13, 14), not of mechanical processing.Open in a separate windowFig. 1.Ordered interfaces after extreme strains. High-resolution transmission electron microscopy micrographs of preferred Cu–Nb interfaces: (A) {338}<443 > Cu||{112}<110 > Nb and (B) {112}<111 > Cu||{112}<110 > Nb. The crystallography of the facet planes is indicated.Additionally, we noticed that they contain a regular array of atomic-scale facets (i.e., the zig-zag morphology). To better understand their origin we developed an atomic-scale (MD) model of this Cu–Nb interface (Fig. S2). The relaxed undeformed equilibrium structure calculated in MD is identical to the HR-TEM observations (34). The two types of facets shown in Fig. 1, {111}Cu//{101}Nb and {001}Cu//{011}Nb, are a consequence of the faceted topology of the {338}Cu and {112}Nb crystallographic planes being joined. They are determined by the global orientation relationship and small angular deviations in the interface–orientation relationship cause a change in the relative length of these facets. Therefore, the faceted interfaces are not a result of residual defects left from numerous interactions with dislocations during severe plastic deformation, but are an intrinsic part of the interface. In other words, these interfaces are not defective with foreign debris as expected, but are atomically perfect.Thus far, we have discovered that extreme mechanical strains can naturally select a preferred interface that possesses atomic order. This counterintuitive result raises fundamental questions of microstructural evolution in plastically deformed metals. Does this preferred interface correspond to a stable state and what variables determined it? Are there others like it? The answers cannot be found by current idealizations of interfaces as obstacles to slip (1, 35, 36) or crystals deforming as part of a polycrystalline network (28). In the following, we explore the special stability conditions that would apply to the dynamic creation of interfaces separated by one-grain layer.Stability is often associated with states of low energy. We begin by using the same atomic-scale Cu–Nb interface model to investigate the formation energy γ of other interfaces. Interfaces are designated by the lattice orientation of the two crystals on either side of the interface with respect to a global frame, orientation relationship of this pair, and the interface planes they join, all of which can be varied independently. Collectively, they describe the interface character. Here we elect to vary character by tilting one crystal relative to another, while covering an orientation space that includes the preferred interface. Fig. 2 shows the energetic landscape versus interface character. In the case shown, the Nb orientation was fixed to {112}<110>, and the Cu orientation was varied. Other similar calculations were performed for different Cu–Nb crystallographic combinations (37). Taken together, the calculations reveal that deep wells in the γ profile correspond to observed preferred interfaces. This can be seen in Fig. 2. Within a narrow orientation range (∼7°), we observe two minimum energy cusps, and these correspond to the two variants of the preferred interface seen in Fig. 1 A and B.Open in a separate windowFig. 2.Preferred interfaces correspond to deep wells in interface formation energy. Molecular dynamics calculation of the variation in interface formation energy with tilt angle about <110 > Cu||<111 > Nb, the direction normal to the micrographs in Fig. 1 (32).Using our atomistic simulations coupled with theoretical methods described in ref. 38, we determined the distribution and characteristics of the interfacial dislocations for each interface in Fig. 2. We find that an interface at the cusp location is associated with the tilt angle that minimizes the value of the Burgers vector of the interfacial dislocations because it best aligns the natural facets of the Cu and Nb planes being joined (37). This is a powerful notion that implies that the preferred interfaces emerging in the Cu–Nb nanocomposites may arise in other bimetal interface material systems.Thus far, our calculations reveal that low formation energy γ is a strong criterion for interface stability. This can be understood on the basis that as strain increases, interface spacing h decreases, and the interface density in the nanomaterial increases; the influence of interface-formation energy naturally grows with increasing strain. However, previous atomic-scale simulations show that there are a few other interface characters (e.g., Kurdjumov–Sachs, Nishiyama–Wasserman γ^KS = 576–586 mJ/m²) that possess even lower formation energies than that associated with the preferred interface reported here (39). Thus, another equally important variable determining mechanical interface stability must coexist with the criterion of low formation energy.To isolate this second key variable, we examine the dynamics of crystal deformation and its role in interface formation. In order for the new interfaces to have the same crystallographic character as the original ones, the original interface must be plastically stable. This means that both the Cu and Nb crystal layers can plastically deform during rolling without reorienting. Previous modeling and experimental studies indicate that slip dynamics within an individual crystal largely dictate its stability against reorientation (27, 28, 35). However, in the presence of interfaces that join one crystal layer to another of dissimilar material, the slip dynamics and resistance to reorientation in the two layers are expected to change. However, how this occurs is unknown. The stability of joined dissimilar crystals in such a highly constrained system has not been modeled before and is challenging to measure experimentally.To explore the plastic stability of an interface, we develop a 3D model of an alternating stack of Cu and Nb single-crystal layers and use the crystal plasticity finite element technique to calculate its dynamic response in deformation (see Supporting Information for more details). The model geometry is designed to authentically represent the actual material for h below the transition point (h < 500 nm). The heart of the model consists of a Cu and Nb crystal joined at a common interface, a bicrystal, with a prescribed crystallographic character (Fig. S3). Applying periodic boundary conditions in three dimensions creates a repeating multilayer architecture with a single interface character. Next, we calculate the lattice rotation of each crystal on either side of the interface under plane strain compression, an idealization of rolling, where the elongation direction coincides with the rolling direction. We use this information to assess stability. To be specific, when straining causes either crystal to rotate, the interface character is altered and hence plastically unstable. As a means of comparing the stabilities of different interfaces, a figure of merit for plastic stability of an interface, ω, is calculated from each simulation, which is given by:where and are the rotation angles (radians) of the lattice of the Cu and Nb crystals from their respective starting orientations due to an imposed strain . In this measure, the limit corresponds to an unstable interface, and the limit to a stable one. For instance, permitting at most small lattice reorientations in each crystal over a large amount of strain, i.e., both and , corresponds to ω ≥ 0.8.Consistent with experiment, in the model, the two crystals joined at an interface are forced to codeform; that is, the interface does not slide or debond during straining. One advantage of the present modeling technique is that it can capture changes in the development of elastic (anisotropic) strains and crystallographic slip accompanying the added constraint of codeformation. To further clarify the effects of codeformation, we carry out a detailed comparison between the plastic stability of the bicrystal with two unbounded individual crystals under the same straining conditions (Supporting Information). The initial orientations of the single crystals are the same as the initial orientations of the crystals on either side of the interface. Like in the calculations of interface energy γ, bicrystal plasticity simulations are performed for a large number of candidate interface characters, chosen based on theoretical grounds or experimental observation. Our results show that the plastic stability of interfaces found in codeforming crystals is not a straightforward superposition of the plastic stabilities of the crystals they join. In fact, most interface characters are not plastically stable (Fig. S4). We find that the reason is that the less stable of the two determines the plastic stability of the interface; the “weaker link” dictates the plastic stability of the pair. This explains why many stable orientations common to single-phase metals are not the same orientations associated with the preferred interfaces after extreme straining.From our calculations, we find that a symmetric distribution of slip on the active slip systems is required for maintaining codeformation and preserving interface orientation. Prior atomic-scale modeling indicates that glide dislocations on slip systems with the highest resolved shear stress can be supplied from faceted interfaces, such as that in Fig. 1 (40, 41).Thus far, our simulations have demonstrated that low formation energy and plastic stability are strong criteria for interface stability. To map out how interfaces compare with respect to both criteria, we plot them in Fig. 3 with respect to their ω and γ on two axes. We find that many interfaces are plastically stable (ω > 0.8), fewer possess relatively low formation energy (γ < 950 mJ/m²), and even fewer correspond to energetic minima (γ ∼ 600–700 mJ/m²). To understand the relative importance of these criteria, we use a black triangle to mark the preferred interface and its closely neighboring variants. The significant outcome is that they all lie exclusively in the region corresponding to both low formation energy and high plastic stability. Interfaces lying farther away from this region are less likely to “survive” extreme straining. From the experimental and simulation results, we conclude that extreme strains naturally select interfaces that are low in formation energy and plastically stable in codeformation, a severe constraint that only a few interfaces satisfy in rolling. This finding also strongly implies that a ubiquitous preferred bimetal interface is an inevitable outcome of extreme straining provided that there are deep wells in interface energy. Broadly speaking, the stability conditions established here are sufficiently fundamental that they can apply to other strain paths and other material systems, such that other emergent interfaces can be forecasted.Open in a separate windowFig. 3.Revealing where emergent interfaces lie: a bimetal interface character stability map. (Top Left) The regime of mechanically stable interfaces. Squares and circles are simulated Cu–Nb interfaces under rolling strains. Triangles indicate those cases corresponding to the observed preferred interfaces. The different variants of preferred interfaces are associated with different orientations of Nb or Cu close in orientation space. Table S1 lists the data corresponding to the points here.As a further test of stability, these nanomaterials were exposed to extreme conditions. We confirmed experimentally that the interface preserves its regular atomic structure under further straining down to h = 20 nm (Fig. 4A). Experiments have demonstrated that the interface structure and parent nanostructure of the h = 20 nm material is retained after 1-h exposure to 0.45, the melting temperature of Cu with little degradation in strength (32) (Fig. 4B). We also report that these interfaces do not develop damaging voids under He-ion irradiation unlike ordinary grain boundaries in Cu (42) (Fig. 4C). The forecasted lifetimes of these bulk nanomaterials, dense with naturally selected interfaces would, therefore, significantly exceed those of their constituents.In summary, we demonstrate that a preferred bimetal interface possessing regular atomic order emerges from extreme mechanical straining of layered nanocomposites. Further, experimental evidence shows that this interface is stable with respect to continued extreme straining, high temperatures, and irradiation. These results are surprising and question current understanding of microstructural evolution during metal working. Using atomic-scale and crystal-plasticity simulation, we reveal that the strong preference is a result of the formation of interfaces nanometers apart during straining. The calculations indicate that the preferred interface is one of few (among the vast space of possible interfaces) that under extreme straining can remain plastically stable while forming interfaces corresponding to a minimum in formation energy. Most significantly, it points to other interfaces that could also emerge in extreme straining and exhibit similar stability properties. Our findings demonstrate that extreme strains can be used as an innovative way toward manipulating interfaces at will for target material properties.     

Cloned IGH VDJ targets as tools for personalized minimal residual disease monitoring in mature lymphoid malignancies; a feasibility study in mantle cell lymphoma by the Groupe Ouest Est d'Etude des Leucémies et Autres Maladies du Sang

Molecular minimal residual disease (MRD) analysis is fast emerging as an essential clinical decision-making tool for the treatment and follow-up of mature B cell malignancies. Current EuroMRD consensus IGH real-time quantitative polymerase chain reaction RQ-PCR assays rely on flow cytometric assessment of diagnostic tumour burdens to construct 'normalized', patient-specific, diagnostic DNA-based MRD quantification standards. Here, we propose a new 'hybrid' assay that relies on plasmid-based quantification of patient-specific IGH VDJ targets by consensus IGH real time (RQ)-PCR, combined with EuroMRD guidelines, for MRD monitoring in lymphoid malignancies. This assay was evaluated for MRD assessment in a total of 273 samples from 29 mantle cell lymphoma (MCL) patients treated within a Groupe Ouest Est d'Etude des Leucémies et Autres Maladies du Sang (GOELAMS) Phase II trial and was feasible, reliable and consistently comparable to gold-standard MRD techniques (99% concordance across all samples including 32 samples within the quantitative range) when analysed in parallel (117 samples). Integrating clinical prognostic parameters and MRD status in peripheral blood at the post-induction stage was predictive of progression-free survival (P = 0·034) thus demonstrating the clinical utility of the approach. Plasmid-based standards for the quantification of IGH VDJ targets are therefore confirmed to offer new opportunities for further standardization and clinical evaluation of MRD-guided management of patients with mature B cell malignancies.     

In vitro comparison of the surface roughness of polymethyl methacrylate and bis-acrylic resins for interim restorations before and after polishing

Statement of problemPolymethyl methacrylate and bis-acrylic based resins are widely used for interim restorations. Their initial surface roughness is important because it determines their aesthetic properties and the potential for biofilm adhesion.PurposeThe purpose of this in vitro study was to assess the surface roughness and morphology of 6 bis-acrylic and 2 polymethyl methacrylate resins widely used for interim dental restorations, both before and after polishing.Material and methodsSpecimens made of different bis-acrylic resins (Protemp 4, Luxatemp Star, Systemp, Telio, Structur Premium, Structur 3) or of polymethyl methacrylate (Unifast Trad, Unifast 3) were polished using a 2-step polishing system (Diatech). The average surface roughness before and after polishing (10 seconds at low speed in dry conditions) was measured by optical profilometry. Atomic force microscopy and scanning electron microscopy were used to analyze surface morphology. The Mann-Whitney and Kruskal-Wallis tests were used to evaluate the differences in roughness among specimens (α=.05), and the Pearson r correlation was computed to assess the relationship between fillers and average surface roughness.ResultsIn the 8 groups evaluated, the roughness significantly increased (P<.001) for Protemp 4 (from 0.12 to 0.50 μm), Luxatemp Star (0.17 to 1.19 μm), Unifast 3 (0.40 to 1.00 μm), Systemp (0.46 to 1.51 μm), Structur 3 (0.85 to 1.06 μm), Structur Premium (1.00 to 1.74 μm), and Telio (1.13 to 1.21 μm), except for Unifast Trad (9.20 to 2.59 μm). Pairwise multiple comparisons identified Protemp 4 as having the smoothest surface before and after polishing, while Unifast Trad was the roughest in both. Atomic force microscopy and scanning electron microscopy observations showed that the surface roughness of bis-acrylic resins was related to their surface morphology and average filler sizes. A positive relation between fillers and roughness was assessed (r=0.345, P<.001).ConclusionsFor the bis-acrylic interim resins, the surface roughness after polishing was correlated to the material used and its filler sizes. Nanofiller-based resins showed the smoothest surfaces. For the polymethyl methacrylate–based resins, the recently marketed Unifast 3 had the lowest overall roughness values.     

Is the coverage of google scholar enough to be used alone for systematic reviews

Background

In searches for clinical trials and systematic reviews, it is said that Google Scholar (GS) should never be used in isolation, but in addition to PubMed, Cochrane, and other trusted sources of information. We therefore performed a study to assess the coverage of GS specifically for the studies included in systematic reviews and evaluate if GS was sensitive enough to be used alone for systematic reviews.

Methods

All the original studies included in 29 systematic reviews published in the Cochrane Database Syst Rev or in the JAMA in 2009 were gathered in a gold standard database. GS was searched for all these studies one by one to assess the percentage of studies which could have been identified by searching only GS.

Results

All the 738 original studies included in the gold standard database were retrieved in GS (100%).

Conclusion

The coverage of GS for the studies included in the systematic reviews is 100%. If the authors of the 29 systematic reviews had used only GS, no reference would have been missed. With some improvement in the research options, to increase its precision, GS could become the leading bibliographic database in medicine and could be used alone for systematic reviews.     

A new case of 8q22.1 microdeletion restricts the critical region for Nablus mask‐like facial syndrome

Microdeletions of 8q21.3–8q22.1 have been identified in all patients with Nablus mask‐like facial syndrome (NMLFS). A recent report of a patient without this specific phenotype presented a 1.6 Mb deletion in this region that partially overlapped with previously reported 8q21.3 microdeletions, thus restricting critical region for this syndrome. We report on another case of an 8q21.3 deletion revealed by array comparative genome hybridization (aCGH) in a 4‐year‐old child with global developmental delay, autism, microcephaly, but without Nablus phenotype. The size of the interstitial deletion was estimated to span 5.2 Mb. By combining the data from previous reports on 8q21.3–8q22.1 deletions and our case, we were able to narrow the critical region of Nablus syndrome to 0.5 Mb. The deleted region includes FAM92A1, which seems to be a potential candidate gene in NMLFS. © 2012 Wiley Periodicals, Inc.     

Risk Factors for Mortality in Hemodialysis Patients: Two-Year Follow-Up Study

Background. End-stage renal disease (ESRD) patients under hemodialysis (HD) have high mortality rate. Inflammation, dyslipidemia, disturbances in erythropoiesis, iron metabolism, endothelial function, and nutritional status have been reported in these patients. Our aim was to identify any significant association of death with these disturbances, by performing a two-year follow-up study. Methods and Results. A large set of data was obtained from 189 HD patients (55.0% male; 66.4 ± 13.9 years old), including hematological data, lipid profile, iron metabolism, nutritional, inflammatory, and endothelial (dys)function markers, and dialysis adequacy. Results. 35 patients (18.5%) died along the follow-up period. Our data showed that the type of vascular access, C-reactive protein (CRP), and triglycerides (TG) are significant predictors of death. The risk of death was higher in patients using central venous catheter (CVC) (Hazard ratio [HR] =3.03, 95% CI = 1.49–6.13), with higher CRP levels (fourth quartile), compared with those with lower levels (first quartile) (HR = 17.3, 95% CI = 2.40–124.9). Patients with higher TG levels (fourth quartile) presented a lower risk of death, compared with those with the lower TG levels (first quartile) (HR = 0.18, 95% CI = 0.05–0.58). Conclusions. The use of CVC, high CRP, and low TG values seem to be independent risk factors for mortality in HD patients.     

Temporal trends in peritonitis rates, microbiology and outcomes: the major clinical complication of peritoneal dialysis

Peritonitis remains a common complication of peritoneal dialysis (PD). The aim of this study was to analyze, in a PD center, long-term temporal trends in peritonitis rates, microbiology and outcomes. We treated 588 cases of peritonitis that occurred during 11,833.6 months at risk. Y-set and twin-bag disconnecting systems were introduced in 1990, mupirocin at the exit site in 2000 and fluconazole prophylaxis in 2005. Vancomycin and ceftazidime were the empiric protocol. Global and 5-year cohort rates were expressed as episodes/patient-year (ep/p-y). A global peritonitis rate reduction was found from 1.02 to 0.47 ep/p-y (p = 0.008). Poisson analyses performed in each of the subgroups of Gram-positive and Gram-negative peritonitis revealed no significant changes over time. No case of vancomycin resistance was identified. There was a downward trend in peritonitis-related hospitalization over time to 0.11 ep/p-y (p ≤ 0.001). Trend analysis showed a favorable, but changing evolution, highlighting the importance of accurate longitudinal PD center registry data and quality control.